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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.

Challenging Issues in the Management of Multiple Sclerosis

To provide neurologists and multiple sclerosis (MS) nurse practitioners with up-to-date clinical evidence, published scientific data and controversies regarding diagnosis and management of MS, and to explore the complex nature of real-world clinical decision making inherent in the contemporary management of MS.

This activity is designed for neurologists and multiple sclerosis nurse practitioners. No prerequisites required.

At the conclusion of this activity, the participant should be able to:

  • List the diagnostic steps in the diagnosis of clinically isolated syndrome, including analysis of spinal fluid, recording evoked potentials, and magnetic resonance imaging (MRI) findings.
  • Describe the role of MRI monitoring as part of assessing disease progression, including analysis of clinical responses to incidental findings suggesting incipient multiple sclerosis (MS) in an asymptomatic patient.
  • Define the issues surrounding available MS therapies, including the goals of reducing disability progression and relapse rates, effect on MRI measures, and effects on cognitive dysfunction.
  • Discuss the indications to switch or combine therapies in patients with progressing MS.
  • Explain how clinical research on the role of the immune system in the pathogenesis of MS may lead to the development of novel immunotherapies. The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 2 hours.

After reading this monograph, participants may receive credit by completing the CME test, evaluation, and receiving a score of 70% or higher.

Release date: August 15, 2008. Expiration date: August 15, 2010.

The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This activity is supported by an educational grant from Biogen Idec and Elan Pharmaceuticals, Inc.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of The Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Course Directors and Participating Faculty reported the following:


Benjamin Greenberg, MD, MHS
Assistant Professor of Neurology
Co-Director, Johns Hopkins Transverse Myelitis Center
Director, Johns Hopkins Encephalitis Center
Department of Neurology
The Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Greenberg reports receiving grants/research support from Accelerated Cure Project, National Multiple Sclerosis Society, and Novartis Pharmaceuticals Corporation; serving as a consultant for Diogenix, Inc, and Genelogic, Inc; and receiving honoraria from Biogen Idec and Teva Neuroscience.

Peter Calabresi, MD
Associate Professor of Neurology
Director, Johns Hopkins Multiple Sclerosis Center
Department of Neurology
The Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Calabresi reports receiving grants/research support from Biogen Idec, Genentech, Inc, Serono, and Teva; and serving as a consultant for Amgen Inc, Eisai Inc, Novartis Pharmaceuticals Corporation, and Vertex Pharmaceuticals.


Bruce Cree, MD, PhD, MCR
Assistant Professor of Neurology
Multiple Sclerosis Center at UCSF
Department of Neurology
University of California San Francisco
San Francisco, California
Dr Cree reports receiving grants/research support from BioMS Medical, EMD Serono, and Genentech, Inc; serving as a consultant for BioMS Medical; and receiving honoraria from Biogen Idec and Teva Neuroscience.

Elliot M. Frohman, MD, PhD, FAAN
Professor of Neurology and Ophthalmology
Irene Wadel & Robert Atha
Distinguished Chair in Neurology
Kenney Marie Dixon Pickens
Distinguished Professor in MS Research
Director, Multiple Sclerosis Program and Clinical Center
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas
Dr Frohman reports serving on the speakers bureau for Biogen Idec, Novartis Pharmaceuticals Corporation, and Teva.

David N. Irani, MD
Associate Professor of Neurology
Staff Neurologist, University of Michigan Multiple Sclerosis Center
University of Michigan Medical School
Ann Arbor, Michigan
Dr Irani reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Norman Kachuck, MD
Associate Professor of Neurology
Chief, Neuroimmunology Division,
Department of Neurology
Director, Multiple Sclerosis Comprehensive Care Center and Research Group
Vice-Chair, Health Sciences IRB
University of Southern California Keck School of Medicine
Los Angeles, California
Dr Kachuck reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Clyde E. Markowitz, MD
Associate Professor of Neurology
Director, Multiple Sclerosis Center at the
Hospital of the University of Pennsylvania
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania
Dr Markowitz reports receiving grants/research support from Bayer Healthcare, Biogen Idec, BioMS Medical, EMD Serono, Genentech, Inc, Novartis Pharmaceuticals Corporation, Opexa Therapeutics, PDL, and Teva; serving as a consultant for Bayer Healthcare, Biogen Idec, EMD Serono, Genentech, Inc, Novartis Pharmaceuticals Corporation, Teva, and Wyeth; and receiving honoraria from Bayer Healthcare, Biogen Idec, EMD Serono, Pfizer Inc, and Teva.

Michael K. Racke, MD
Professor and Chair, Department of Neurology
The Helen C. Kurtz Chair in Neurology
The Ohio State University Medical Center
Columbus, Ohio
Dr Racke reports receiving grants/research support from the National Institutes of Health and National Multiple Sclerosis Society; and receiving honoraria from and serving on the speakers' bureau for Berlex, Serono, and Teva Neuroscience.

Timothy L. Vollmer, MD
Professor of Neurology
Co-Director, Rocky Mountain Center for MS Care and Research
Department of Neurology
University of Colorado Health Sciences Center
Aurora, Colorado
Dr Vollmer reports receiving grants/research support from Bayer, Biogen Idec, Daichii Sankyo, Novartis Pharmaceuticals Corporation, PDL, Serono, and Teva USA; serving as a consultant for Bayer, Biogen Idec, Serono, and Teva USA; receiving honoraria from Biogen Idec, NBC Universal, and Teva USA; and serving on the speakersÕ bureau for Bayer, Biogen Idec, and Teva USA.

Notice: The audience is advised articles in this CME activity contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Cree and Dr Vollmer glatiramer acetate.
Dr Frohman and Dr Greenberg azathioprine, methotrexate, methylprednisolone sodium succinate, mycophenolate, and mycophenolate mofetil.
Dr Irani and Dr Markowitz alemtuzumab, cladribine, cyclophosphamide, daclizumab, glatiramer acetate for primary progressive MS (approved for relapsing-remitting MS), interferon b-1b for secondary progressive MS in the United States (approved for secondary progressive MS in Europe and relapsing-remitting MS in the United States), intravenous immunoglobulin, methotrexate, and rituximab; experimental treatments not yet approved for any indication are autologous T-cell vaccination in patients with clinically isolated syndrome or relapsing-remitting MS, BG-12, fingolimod (FTY720), laquinimod, and MBP8298.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Challenging Issues in the Management of Multiple Sclerosis
Benjamin Greenberg, MD, MHS,* and Peter Calabresi, MD

In September 2007, a unique program, called "A Multisite Think Tank on the Challenges of Multiple Sclerosis," invited 200 community neurologists to meetings held across the United States. This program, presented by The Johns Hopkins University School of Medicine, was designed to serve 2 purposes: to examine clinical and scientific data recently published and to give community neurologists a platform to discuss the complex nature of making clinical decisions inherent in the modern management of multiple sclerosis (MS). Although evidence-based data are available to support some of the difficult clinical decisions made by community neurologists, much remains uncertain. Interaction among academic faculty and regional community clinicians allowed for dialogue and exploration of several controversial issues in the diagnosis, prognosis, treatments, and practice trends in patients with or at risk for MS. 

The underlying motivation for this program was to reach out to experienced community neurologists who make difficult decisions with patients who are somewhere along the continuum from uncertain neurologic symptoms to high risk for MS to clinically definite MS (CDMS). Clinicians report difficulty in determining the best course of action for patients with minimal symptoms and an uncertain prognosis, and there is often a sense of disconnect between academic MS centers and community neurologic practice.

The real-world problem is that neurologists see patients who do not always fit into a clean-cut neurologic profile. There are conflicting recommendations and practice patterns for evaluating and treating patients who present with first symptoms of demyelinating disease, but who do not yet fulfill criteria for CDMS. Practitioners and patients must weigh various sets of limited data regarding rates of conversion to MS, clinical efficacy of early treatment, and a relative lack of data regarding long-term outcomes of patients treated early in the course of the disease. During this program, academic and community neurologists reviewed available data to try and discern current practice patterns and determine where consensus could be built.

This issue of Johns Hopkins Advanced Studies in Medicine, which discusses challenging issues in the management of MS was developed from the discourse that occurred at the Multisite Think Tank meetings. The articles that follow, written by our faculty, summarize lessons learned from the seminars, which are a synthesis of faculty presentations, audience questions and comments, and insights gleaned from feedback to case presentations. The meeting attendees, drawn from across the country from diverse backgrounds and with various levels of experience (from fellows in training to neurologists of 40+ years in practice), and working in various types of community practices, presented to us at the meetings their concerns and challenges in partnering patients through the difficult choices that must be made on a regular basis as part of the management of MS.

Overview of the Field

Multiple sclerosis is a chronic progressive disease of the central nervous system (CNS) resulting from inflammatory insults and degeneration that occurs over time. It is more common in whites than in persons of other races, more common in women than in men, and is most prevalent between the ages of 20 to 50 years. The condition causes progressive disability, particularly in areas of muscle control and strength, vision, balance, sensation, emotional well-being, and cognition. It represents a terrifying diagnosis for patients, who often progress to disability. Patients often lose the ability to walk, become incontinent of urine, or have disabling fatigue, confusion, and depression. Patients with or at risk of MS rely on their neurologists to guide them through years of living with uncertainty about the disease and its treatments, to help them to maintain hope and motivation, and to prepare and fortify them in the face of disease progression.

Although recent advances in the treatment of MS have been truly remarkable, the clinical community continues to confront some of the same questions that have challenged neurologists for the past 25 years. In describing the pathology of MS, it appears that an unidentified factor is responsible for triggering an immunologic f"attack" on myelin sheaths, causing interference in nerve impulse conduction with a variable clinical presentation relative to where in the CNS the injury is occurring. Indeed, clinical manifestations of MS can affect nearly any part of the nervous system and may mimic other conditions. It is theorized that reversal of inflammation and even remyelination may occur and lead to improvement in clinical function; however, once axonal damage has occurred, reversal becomes much more difficult. Unfortunately, axonal damage may occur at the very early stages of disease or at any point or multiple points along the disease. The extent of axonal damage among patients with MS is highly variable, but it does appear that the accumulation of axonal destruction underlies clinical progression. Epidemiologic data show that the large majority of patients with MS (approximately 85%) will have relapsing-remitting MS (RRMS) whereas approximately 10% to 15% of patients with MS will have primary progressive disease.

The diagnosis and management of patients with MS has undergone a remarkable change over the last 2 decades with the introduction of new imaging modalities (eg, magnetic resonance imaging [MRI]), as well as through the use of successful disease-modifying therapies. The McDonald criteria for diagnosis, which were promulgated in 2001 and updated in 2005, have advanced clinicians' ability to characterize differing clinical presentations of MS and to establish a definitive diagnosis. Regrettably, no treatment has proven efficacious at reversing disease progress once the diagnosis is certain or even highly probable. Treatment decisions are clouded by a lack of comparative data among currently approved MS agents, and it remains challenging to characterize treatment failure versus disease relapse, further hindering rational treatment decisions. Adverse effects of treatment in addition to adherence difficulties also complicate clinical assessments.

Despite the limitations and challenges, currently approved agents do reduce disease activity and improve quality of life for patients with relapsing MS. Moreover, the benefits of early treatment are becoming increasingly apparent as evidence mounts to show that episodes of inflammation contribute to permanent axonal damage.

Controversies in Multiple Sclerosis

The Multisite Think Tank meetings focused on areas of particular concern to community clinicians that also present controversy within the field at large. It is recognized that there is a critical need for guidance and consensus regarding several issues, including the definition and identification of treatment success and failure; evidence-based treatment algorithms to guide clinicians choosing among current therapeutic strategies; the best clinical approach to disease monitoring through the use of imaging studies; and a glance toward therapeutic horizons and state of clinical research. The discussion and dialog that took place during the Multisite Think Tank are reflected in the following 4 articles. The audience response system (ARS) provided a question-and-answer forum to survey community neurologistsÕ opinions on a wide range of topics in MS disease management (Table).

Clinically Isolated Syndrome

In their article, Clinically Isolated Syndrome: Evaluation, Risk Stratification, and Treatment Decisions, Bruce Cree, MD, PhD, MCR, and Timothy L. Vollmer, MD, discuss the evaluation of and treatment options for patients with clinically isolated syndrome (CIS). These are solitary, acute or subacute demyelinating inflammatory events involving the optic nerve, brain, spinal cord, or brain stem. Common CIS presentations include optic neuritis, brain stem, and spinal cord syndromes. CIS events are strong predictors for the development of MS, but diagnosis of CDMS requires evidence of neurologic events and lesions separated in both time and space. Furthermore, an alternative diagnosis should be considered when patients who present with a CIS are aged younger than 15 or older than 60 years, or when symptoms are limited to the posterior fossa craniocervical junction or spinal cord.

There is evidence that axonal transection, which may be clinically silent at outset, occurs quite early in the disease process, perhaps even in patients with CIS. These data have raised concern about the expected outcomes of patients presenting with first symptoms of MS. Prospective trial data offer a clinical framework for identifying prognosticating factors for conversion from CIS to CDMS, and long-term data show that most, but certainly not all, patients presenting with CIS go on to some form of MS. This article addresses challenging clinical questions, such as: How should we evaluate these patients and stratify their risks? Who is more or less likely to go on to develop multiphase disease? What is the evidence that early intervention in patients with CIS will alter patient outcomes? What clinical or pathologic correlations should clinicians use to weigh the risks and benefits of early treatment in this patient set?

MRI in Multiple Sclerosis

It is well established that MS is significantly more active on MRI than it is in terms of clinical presentation. Thus, the majority of patients who are experiencing an initial event already show old (non-enhancing) lesions on MRI. Because of its varied clinical presentation and course, practitioners are increasingly relying on alternative routes to diagnose and monitor the progression of MS. In their article, Monitoring Disease Progression: Incorporating MRI and New Modalities in Clinical Decision Making, Norman Kachuck, MD, and Michael K. Racke, MD, review the historical, current, and emerging use of diagnostic studies, including conventional MRI, high-field- strength MRI, magnetic resonance spectroscopy, functional MRI, spinal cord MRI, magnetization transfer ratio, diffusion-weighted and diffusion tensor imaging, and optical coherence tomography.

Advances in technology have improved the ability to diagnose and monitor disease progression in patients with MS. Although clinical evidence remains the core of diagnosis of MS, there is growing consensus that MRI and adjunctive studies should play an increasingly important role in everyday clinical practice for community-based practitioners. Imaging studies are useful in diagnosis of disease, disease monitoring, and monitoring therapeutic efficacy of treatments, as well as in clinical trials. This article reflects the sentiment of Multisite Think Tank participants who are becoming increasingly positive about the use of MRI in clinical practice in terms of their ability to manage patients with MS with greater confidence. Although there is a desire to treat the patient and not the MRI among physicians, it is increasingly clear that sequential MRI studies in addition to newer modalities provide important information about the future clinical status of patients with MS. Yet, there remains a gap between research imaging technologies at use in academic centers and those that are routinely available. These modalities need to be validated before being dispersed into widespread use.

Defining Success in Multiple Sclerosis: Treatment Failures and Nonresponders

In clinical settings, measures of ongoing disease activity are determined by a composite of relapse rate, periodic MRI findings, the clinical neurologic examination, disability scores (Expanded Disability Status Scale), functional assessments, and the patient's assessment of his or her level of functioning and well-being. Nonetheless, the process of evaluating treatment efficacy is science and art. Once a patient with MS is initiated on therapy, it is the clinician's task to determine success or failure of the regimen. One threshold for determining treatment failure is exceeding the baseline rate of attacks before treatment intervention. Disease activity in a patient on therapy might variously be described as breakthrough disease, treatment failure, or even treatment success in cases where disease progress continues at a slower pace. Moreover, the definition of failure and success is not static within a patient, nor uniformly applicable among patients with varying demographic characteristics. The issue of quality of life remains both individual and personal.

In their article, Defining Success in Multiple Sclerosis: Treatment Failures and Nonresponders, Benjamin Greenberg, MD, MHS, and Elliot M. Frohman, MD, PhD, FAAN, describe the state of prognosis and treatment decision making in MS. Although population natural history studies are useful for defining relative treatment success guidelines, it is difficult to apply these standards to individual patients. In general, untreated patients experience 1 relapse per year on average. Yet, there is also evidence that patients will go through relative periods of disease activity and remission. The authors offer various definitions of breakthrough disease, including unacceptable (defined jointly by clinician and patient) clinical or radiographic evidence of activity. They discuss predictors of sustained disability, brain imaging features, immunologic markers, neurologic features, symptoms, relapse rates and severity, and the importance of clinical follow-up and treatment adherence. When faced with a patient who fits the portrait of a nonresponder, the clinician must choose among divergent strategies, including continuing current therapy, changing the dose of a current medication, switching therapies, or introducing combination therapy. The limited evidence for each of these strategies was discussed and debated.

Therapeutic Frontiers in Multiple Sclerosis

New therapies for MS are under investigation in controlled clinical trials; however, recruitment to trials from the community remains somewhat blunted. A large majority of community neurologists participating in the Multisite Think Tank felt that most patients should have a reasonable trial of existing approved therapies before being referred to clinical trials; this is particularly true for patients with RRMS, and somewhat less so for patients with primary and secondary progressive MS. Similarly, participants were more reluctant to see patients with RRMS enter placebo-controlled trials. Some of the barriers that limit community referral into trials are quite practical, such as lack of information about trials, cumbersome inclusion and exclusion criteria, not knowing how to refer patients, and encountering difficulties in ensuring a smooth transition into trials.

In their article, Multiple Sclerosis: Therapeutic Frontiers and Progressive Disease, David N. Irani, MD, and Clyde E. Markowitz, MD, review clinical trial data and provide a frank discussion of the strengths and weaknesses of evidence-based medicine in treatment of MS, with an emphasis on the future of MS therapeutics. Currently, there are 15 to 20 compounds being developed and investigated for the treatment of MS, with a particular focus on advancing therapeutic options for the treatment of progressive disease. The authors review data from several studies, including the European Study Group, North American Secondary-Progressive MS Study, SPECTRIMS Study (Secondary Progressive Efficacy Clinical Trial of Rebif in MS Study), IMPACT trial, PROMISE, and Mitoxantrone in Secondary-Progressive Multiple Sclerosis (MIMS) study. Future therapeutics are presented and include an overview of the field, an update on novel compounds entering phase III studies, including monoclonal antibody-based agents, oral agents, and intravenous synthetic peptides.

Summary: Lessons Learned from the Multisite Think Tank

The Multisite Think Tank was thought provoking and rewarding for faculty and participants alike. As Course Directors, we were very gratified with the participation by community neurologists and wish to thank everyone who participated. Participant contributions were translated into a data set of responses through ARS feedback, comments, and evaluations. The set of articles comprising this monograph is indebted to the contributions of those physicians.

Although many of the questions posed to the audience during the Multisite Think Tank received mixed responses (Table), participating community clinicians were almost unanimous in their responses to specific questions. For example, 100% of participants reported valuing the use of baseline MRI in patients presenting with CIS, in terms of the decision to start disease- altering therapies and in discussing prognosis with their patients; in addition, it was interesting to note that 90% reported that they would change therapies in a patient with signs of relapse and new MRI lesions.

One of the most important take-home messages from the Multisite Think Tank experience is the importance of the patient-clinician alliance in the community. Clinicians partner with patients to define ambiguous concepts in MS, such as breakthrough disease and treatment failure, and to decide when and if therapies should be initiated, discontinued, changed, or otherwise modified. Community clinicians have a great awareness of what treatment effects are most likely to result in poor treatment compliance and how patients respond in the early months of a new therapy. Because disease progression remains hard to predict, community neurologists are becoming increasingly interested in using imaging studies and discussing disease-modifying therapies in patients earlier. In addition, they are eager for clinical trials to be performed that can produce therapeutically relevant information (eg, drug-to-drug comparison trials). Trial design should be more responsive to the needs of community clinicians, who remain the most effective advocates for patients with MS.


This continuing medical education monograph was developed from "The Multisite Think Tank on the Challenge of Multiple Sclerosis," a series of 8 regional meetings held on September 8, 2007, in 4 cities (Chicago, IL; Dallas, TX; Dana Point, CA; and Scottsdale, AZ) and on September 29, 2007, in an additional 4 cities (Detroit, MI; Minneapolis, MN; Philadelphia, PA; and Washington, DC). The Course Directors and faculty would like to thank the 197 community neurologists who attended these meetings as fellow faculty. We would also like to thank Dr Linda Gerber and her team at the Biostatistics and Research Methodology Core at Weill Cornell Medical College in New York, NY, for their help with the data resulting from the use of a keypad question system. The initiative was funded by an educational grant from Biogen Idec and Elan Pharmaceuticals, Inc.

*Assistant Professor of Neurology, Co-Director, Johns Hopkins Transverse Myelitis Center, Director, Johns Hopkins Encephalitis Center, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Associate Professor of Neurology, Director, Johns Hopkins Multiple Sclerosis Center, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Address correspondence to. Benjamin Greenberg, MD, MHS, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Pathology 627, Baltimore, MD 21287. E-mail:

The content in this monograph was developed with the assistance of a medical writer. Each author had final approval of his article and all its contents.

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